A novel TMSI-mediated synthesis of Hantzsch 1,4-dihydropyridines at ambient temperature

Article abstract of DOI:10.1016/S0040-4039(03)00813-X

The synthesis of various substituted Hantzsch 1,4-dihydropyridines has been achieved using the classical Hantzsch procedure and modified Hantzsch conditions for the first time at room temperature in the presence of iodotrimethylsilane (TMSI) generated in situ in CH₃CN, in excellent yields.

Full text of DOI:10.1016/S0040-4039(03)00813-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 4129–4131
A novel TMSI-mediated synthesis of Hantzsch
1,4-dihydropyridines at ambient temperatureꢀ
Gowravaram Sabitha,* G. S. Kiran Kumar Reddy, Ch. Srinivas Reddy and J. S. Yadav
Organic Chemical Sciences, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 10 February 2003; revised 13 March 2003; accepted 21 March 2003
Abstract—The synthesis of various substituted Hantzsch 1,4-dihydropyridines has been achieved using the classical Hantzsch
procedure and modified Hantzsch conditions for the first time at room temperature in the presence of iodotrimethylsilane (TMSI)
generated in situ in CH3CN, in excellent yields. © 2003 Elsevier Science Ltd. All rights reserved.
Hantzsch 1,4-dihydropyridines (1,4-DHPs) are well
known as Ca2+ channel blockers, and have emerged as
one of the most important classes of drugs for the
treatment of cardiovascular diseases, including hyper-
tension.1 The DHP heterocyclic ring is a common fea-
ture of various bioactive compounds such as
vasodilator, bronchodilator, antiatherosclerotic, antitu-
mor, geroprotective, hepatoprotective and antidiabetic
agents.2 Recent studies have revealed that 1,4-DHPs
exhibit several other medicinal applications which
include neuroprotectant3a and platelet anti-aggregra-
tory activity,3c in addition to acting as a cerebral antiis-
chemic agent in the treatment of Alzheimer’s disease3c
and as a chemosensitizer in tumor therapy.3d These
examples clearly demonstrate the remarkable potential
of novel DHP derivatives as a source of valuable drug
candidates. A recent computational analysis of the
comprehensive medicinal chemistry database found the
DHP framework to be among the most prolific chemo-
types found. Thus, the synthesis of this heterocyclic
nucleus is of continuing interest. The success of these
calcium antagonists has led to the development of novel
synthetic strategies to improve their classical methods
of preparation. Microwave activation stands among the
alternative routes proposed during the past decade due
to the drastic reduction of reaction times.4 More than a
century ago the first 1,4-DHPs were obtained by
Hantzsch.5 This reaction involves a one-pot condensa-
tion of an aldehyde with ethyl acetoacetate, and ammo-
nia either in acetic acid or refluxing in alcohol for a
longer time. However, the yields of 1,4-DHPs obtained
by the Hantzsch method are generally low. Even
though a number of modified methods6 under improved
conditions have been reported, many of them suffer
from drawbacks such as unsatisfactory yields, high
temperatures and long reaction times. Thus, the devel-
opment of an efficient and versatile method for the
preparation of Hantzsch 1,4-DHPs is an active ongoing
research area and there is scope for further improve-
ment toward milder reaction conditions and improved
yields. The versatility of iodotrimethylsilane as a useful
reagent in organic synthesis is well established.7 As a
continuation of our studies of TMSI,8 we report in this
communication a novel and efficient synthesis of
Hantzsch 1,4-dihydropyridines by the classical
Hantzsch procedure (Scheme 1) and as well as by a
Scheme 1.
Keywords: TMSI; Hantzsch 1,4-dihydropyridines; one-pot condensation; ambient temperature.
ꢀ IICT Communication No: 030206.
* Corresponding author. Fax: +91-40-27160512; e-mail: sabitha@iict.ap.nic.in
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00813-X

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G. Sabitha et al. / Tetrahedron Letters 44 (2003) 4129–4131
stituents were converted into the expected 1,4-DHPs in
good to excellent yields and the results are summarized
in Table 1. All reactions were clean and efficient at
room temperature and the products were obtained
within 6–8 h in good yields.9 To the best of our
knowledge, this is the first report of the preparation of
1,4-DHPs at ambient temperature based on the
Hantzsch procedure.
modified Hantzsch procedure (Scheme 2) using TMSI
in CH3CN at ambient temperature.
Thus, the condensation of 1 equiv. of benzaldehyde 1a
with 2 equiv. of ethyl acetoacetate 2a and 2 equiv. of
NH4OAc in the presence of TMSI (generated in situ
from TMSCl+NaI) resulted in the formation of
Hantzsch 1,4-dihydropyridine 3a (Scheme 1, method
A). The reaction was complete in 6 h at room tempera-
ture and the product was isolated by usual work-up, in
80% yield, with high purity. Under similar conditions
various substituted aromatic and aliphatic aldehydes
carrying either electron-donating or -withdrawing sub-
To examine the versatility of the reagent, the prepara-
tion of 1,4-DHPs was tested using a modified Hantzsch
procedure. Treatment of 1 equiv. of benzaldehyde 1a
with 2 equiv. of ethyl aminocrotonate 4 in the presence
Scheme 2.
Table 1. TMSI-mediated synthesis of dihydropyridines under Hantzsch and modified Hantzsch conditions

G. Sabitha et al. / Tetrahedron Letters 44 (2003) 4129–4131
4131
of TMSI generated in situ in CH3CN afforded the
corresponding 1,4-DHP 3a (Scheme 2, method B) in
85% yield at room temperature. Table 1 represents the
generality of the present procedure for the synthesis of
various substituted 1,4-DHPs including an example pre-
pared from an aliphatic aldehyde (Table 1, compound
3f). All the reactions proceeded smoothly at room
temperature to afford the products in good to high
yields within 2–2.5 h.9
Reddy, B. V. S.; Reddy, P. T. Synth. Commun. 2001, 31,
425–430; (c) Alajarin, R.; Vaquero, J. J.; Navio, J. L. G.;
Alvarez-Builla, J. Synlett 1992, 297–298; (d) Cotterill, I.
C.; Usyatinsky, A. Y.; Arnold, J. M.; Clark, D. S.;
Dordick, J. S.; Michels, P. C.; Khmelnitsky, Y. L. Tetra-
hedron Lett. 1998, 39, 1117–1120.
5. Hantzsch, A. Justus Liebigs Ann. Chem. 1882, 1, 215.
6. (a) Gordeev, M. F.; Patel, D. V.; Gordon, E. M. J. Org.
Chem. 1996, 61, 924–928; (b) Breitenbucher, J. G.;
Figliozzi, G. Tetrahedron Lett. 2000, 41, 4311–4315; (c)
Ohberg, L.; Westman, J. Synlett 2001, 1296–1298; (d)
Anderson, A. G., Jr.; Berkelhammer, G. J. Am. Chem.
Soc. 1958, 80, 992–999; (e) Phillips, A. P. J. Am. Chem.
Soc. 1949, 71, 4003–4007; (f) Maquestiau, A.; Maeyence,
A.; Eynde, J.-J. V. Tetrahedron Lett. 1991, 32, 3839–3840.
7. For a review, see: Olah, G. A.; Narang, S. C. Tetrahedron
1982, 38, 2225–2277.
All the products prepared from these two routes were
characterized by their spectral data and known com-
pounds by comparison with reported data. The advan-
tages of the present protocols are the shorter reaction
times at room temperature, mild reaction conditions
and due to the high reactivity of the reagent the prod-
ucts are obtained in high yields. In addition to this,
good yields of 1,4-DHPs were obtained from o-substi-
tuted benzaldehydes, which is not the case in existing
procedures. Another important aspect is that various
functionalities such as ether, nitro, hydroxy, halide,
etc., survived under the present reaction conditions.
The best results were obtained using 1 equiv. of TMSCl
and 1 equiv. of NaI.
8. (a) Sabitha, G.; Yadav, J. S. Synth. Commun. 1998, 28,
3065–3071; (b) Sabitha, G.; Abraham, S.; Reddy, B. V. S.;
Yadav, J. S. Tetrahedron Lett. 1999, 40, 1569–1570.
9. Experimental:
Synthesis of 1,4-DHPs 3a–n: Aldehyde 1 (5 mmol), b-keto
ester 2 (10 mmol) and NH4OAc (10 mmol) were dissolved
in acetonitrile (10 mL) and stirred at room temperature.
To this, TMSCl (5 mmol) was added dropwise and then
NaI (5 mmol) was added in one portion and the reaction
mixture was stirred at room temperature for an appropri-
ate time (Table 1). After completion of the reaction as
indicated by TLC, it was poured into ice cold water and
extracted with ethyl acetate. The organic layer was washed
with sodium thiosulphate and water then dried and con-
centrated in vacuo. The crude products were purified by
column chromatography using silica gel (60–120 mesh)
and eluted with ethyl acetate–hexane (3:7) to afford 1,4-
DHPs in 73–80% yields.
In conclusion, we have demonstrated for the first time a
novel synthetic protocol enabling access to Hantzsch
1,4-DHPs in good to excellent yields in short reaction
times at room temperature. We believe that the present
improved modification is a convenient and attractive
alternative to the existing methods for the synthesis of
1,4-DHPs.
Acknowledgements
Synthesis of 1,4-DHPs 3a–g, 3o–t: Aldehyde 1 (5 mmol)
and ethyl/methyl aminocrotonate 4 (10 mmol) were sus-
pended in acetonitrile (10 mL). To this suspension, NaI (5
mmol) in one portion, then TMSCl (5 mmol) were added
and the reaction mixture was stirred at room temperature
for 2–2.5 h. After completion of the reaction as indicated
by TLC, the reaction mixture was quenched with ice cold
water and extracted with ethyl acetate. The organic layer
was washed with sodium thiosulphate and water then
dried and concentrated in vacuo and the resulting crude
products were recrystallized using EtOAc: pet ether (9:1)
to afford pure products 3a–g, 3o–t in 78–85% yields.
NMR data for selected compounds: Entry 3e: 1H NMR
(200 MHz, CDCl3): l 0.95 (t, 6H, J=8.2 Hz), 2.29 (s, 6H),
3.92 (q, 4H, J=8.2 Hz), 5.55 (brs, 1H), 5.76 (s, 1H),
7.30–7.55 (m, 4H), 7.60 (d, 1H, J=8.68 Hz), 7.72 (d, 1H,
J=8.6 Hz), 8.55 (d, 1H, J=8.6 Hz); 3f: 1H NMR (200
MHz, CDCl3): l 0.75 (d, 6H, J=7.2 Hz), 1.30 (t, 6H,
J=8.2 Hz), 1.55 (m, 1H), 2.30 (s, 6H), 3.92 (d, 1H, J=7.2
G.S.K.K.R. would like to thank the CSIR, and Ch.S.R.
would like to thank the UGC, New Delhi, for the
award of fellowships.
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